The recent large-scale projects on human single nucleotide polymorphisms (SNP) provided a wealth of information to help uncover the relationship between human genetic variation and disease. A number of tools aims to predict if a SNP will be deleterious for a protein by using physical and comparative criteria. On the other hand,"amutation may not be deleterious for a protein, but change the way it interacts with its interaction partners. Hence, a complementary approach to find mutations that effect interactions are needed. This proposal maps out a systematic search for finding genetic variations that disrupt the interaction behavior of a protein. First, a correlated mutation analysis will be employed to find amino acid residues that mediate interaction between known interacting protein pairs. This will be followed by an experimental verification of the putative interacting residues using yeast two hybrid method (Y2H). Then, SNPs that are located at these residues will be identified and finally how the genetic variation in these residues disrupt protein-protein interactions will be experimentally analyzed using Y2H. The proposed research plan will find subtle variations in human proteins that influence how they interact with other proteins in the cell. These identified variations will offer insights for finding the causes of diseaes and also add a new dimension to our understanding of the relationship between genetic variation and cellular networks.